Fungicides

ABSTRACT

The invention provides the use in combating fungi of compounds of general formula (I) wherein R 1  is hydrogen, hydroxy, acyl, acyloxy, optionally substituted amino, R a , R a   3 Si, R a S or R a O, where R a  is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl or optionally substituted heterocyclyl; R 2  has the same meaning as R a  or can be hydrogen; Z is oxygen or sulfur, M is a thiophene ring, and R 3  and R 4 , which may be the same or different, have the same meaning as R a  or can be optionally substituted amino, hydrogen, halogen, cyano, nitro or a group OR c  or S(O) m R c , where R c  has the same meaning as R a  or is hydrogen or acyl and m is 0, 1 or 2; or R 3  and R 4  together with the atoms to which they are attached form an optionally substituted carbocyclic or heterocyclic ring; together with tautomers of compounds where R 1  is hydrogen.

The invention relates to the use of compounds in combating fungi inplants.

In Bull. Soc. Chim. France, 1970, (10), 3630-6, there are disclosedcertain thienopyrimidines. We have discovered that at least one of thesecompounds has utility in combating fungi.

In WO97/02262 there are disclosed thienopyrimidine derivatives, usefulas fungicides, substituted at the 2-position by an oxygen, sulfur ornitrogen.

In EP0665224 there are disclosed two specific 2-benzyl substitutedthienopyrimidines useful as fungicides and/or herbicides.

In WO99/14202, published after the priority date of this application,there are disclosed 2-substituted thienopyrimidines useful asfungicides.

The invention provides the use in combating fungi of compounds ofgeneral formula I

wherein

R¹ is hydrogen, hydroxy, acyl, acyloxy, optionally substituted amino,R^(a), R^(a) ₃Si, R^(a)S or R^(a)O, where R^(a) is optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkenyl, optionally substituted aryl or optionallysubstituted heterocyclyl;

Z is oxygen or sulfur;

M is a thiophene ring; and

R³ and R⁴, which may be the same or different, have the same meaning asR^(a) or can be optionally substituted amino, hydrogen, halogen, cyano,nitro or a group OR^(c) or S(O)_(m)R^(c), where R^(c) has the samemeaning as R^(a) or is hydrogen or acyl and m is 0, 1 or 2; or R³ and R⁴together with the atoms to which they are attached form an optionallysubstituted carbocyclic or heterocyclic ring;

together with tautomers of compounds where R¹ is hydrogen.

Most of the above compounds are novel, and accordingly the inventionincludes any novel compounds of formula I as defined above, includingin, 7-bromo-3-methyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one.

Any alkyl group present in the molecule is preferably of 1 to 10 carbonatoms, especially of 1 to 7 carbon atoms, and particularly of 1 to 5carbon atoms.

Any alkenyl or alkynyl group present in the molecule is preferably of 2to 7 carbon atoms, for example allyl, vinyl or propargyl.

Any cycloalkyl, cycloalkenyl or cycloalkynyl group present in themolecule is preferably of 3 to 7 carbon atoms, especially cyclopropyl,cyclopentyl, cyclohexyl or cyclohexenyl.

Substituents, when present on any alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl cycloalkynyl moiety may for example be halogen, cyano,optionally substituted alkoxy, optionally substituted alkylthio,mercapto, hydroxy, nitro, optionally substituted amino, acyl, acyloxy,acylthio, optionally substituted phenyl, optionally substitutedheterocyclyl, optionally substituted phenylthio, optionally substitutedphenoxy, optionally substituted heterocyclyloxy, optionally substitutedheterocyclylthio.

Cycloalkyl, cycloalkenyl, cycloalkynyl groups may also be substituted byoptionally substituted alkyl, alkynyl or alkenyl and vice versa.

Substituents when present on any phenyl or heterocyclyl group may be thesame or different and include R^(a)—(X)_(n)—, (where R^(a) is as definedabove, X is oxygen or sulfur and n is 0 or 1), optionally substitutedamino, hydroxy, halogen, cyano, nitro, acyl, or two adjacent groupstogether with the carbon atoms to which they are attached can form anoptionally substituted benzo or heterocyclic ring. Heterocyclyl groupsmay also be substituted by double-bonded substituents such as oxo orimino.

The term heterocyclyl includes both aromatic and non-aromaticheterocyclyl groups. Heterocyclyl groups are generally 5, 6 or7-membered rings containing up to 4 hetero atoms selected from nitrogen,oxygen and sulfur. Examples of heterocyclyl groups are furyl, thienyl,pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, dioxolanyl, oxazolyl,thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl,pyrazolinyl, pyrazolidinyl, isoxazolyi, isothiazolyl, oxadiazolyl,triazolyl, thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxanyl,morpholino, dithianyl, thiomorpholino, pyridazinyl, pyrimidinyl,pyrazinyl, piperazinyl, triazinyl, thiazolinyl, benzimidazolyl,tetrazolyl, benzoxazolyl, imidazopyridinyl, 1,3-benzoxazinyl,1,3-benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl,quinazolinyl, quinoxalinyl, sulfolanyl, dihydroquinazolinyl,benzothiazolyl, phthalimido, benzofuranyl, azepinyl, oxazepinyl,thiazepinyl, tetrahydrofuryl, diazepinyl and benzodiazepinyl.

Amino groups may be substituted for example by one or two R¹ groups, ortwo substituents can form a ring, preferably a 5 to 7-membered ring,which may be substituted and may contain other heteroatoms, for examplemorpholine, thiomorpholine, or piperidine. This ring can be substitutedas for heterocyclyl.

The term acyl includes the residue of sulfur and phosphorus-containingacids as well as carboxylic acids. Examples of acyl groups are thus—COR⁵, —COOR⁵, —CXNR⁵R⁶, —CON(R⁵)OR⁶, —COONR⁵R⁶, —CON(R⁵)NR⁶R⁷, —COSR⁵,—CSSR⁵, —S(O)_(p)R⁵, —S(O)₂OR⁵, —S(O)_(p)NR⁵R⁶, —P(═X)(OR⁵)(OR⁶),—CO—COOR⁵, where R⁵, R⁶ and R⁷, which may be the same or different, arehydrogen, optionally substituted alkyl, optionally substitutedcycloalkyl, optionally substituted cycloalkenyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted phenylor optionally substituted heterocyclyl, or R⁵ and R⁶, or R⁶ and R⁷,together with the atom(s) to which they are attached can form a ring, pis 1 or 2 and X is O or S.

We have found that compounds of the inventor wherein Z is oxygen areparticularly effective in combating fungi.

Preferred R¹ groups are hydrogen, 2-oxotetrahydrofuranyl or optionallysubstituted alkyl. In particular when R¹ is optionally substituted alkylwe have found C₁-C₅ alkyl groups, e.g. methyl, to be especiallypreferred. Preferred substituents are alkoxycarbonyl, alkanoyloxy, cyanoand phenyl, itself optionally substituted by alkyl, alkoxy, haloalkyl orhalogen.

R³ and R⁴ can be the same or different and are preferably hydrogen,halogen or optionally substituted alkyl. It is generally desirable thatone of R³ and R⁴. is halogen, especially bromine or chlorine, andparticularly bromine, and the other is hydrogen. In particular when R³or R⁴ is optionally substituted alkyl, we have found C₁-C₅ alkyl groups,especially tert.-butyl, to be most active. When R³ or R⁴ is substitutedalkyl, preferred substituents are halogen, e.g. trifluoromethyl.

Although good activity has been shown for each fused ring system,generally the thieno[3,2-d]pyrimidine ring system is preferred.

The compounds of the invention have activity as fungicides, especiallyagainst fungal diseases of plants, e.g. mildews and particularly cerealpowdery mildew (Erysiphe graminis) and vine downy mildew (Plasmoparaviticola), rice blast (Pyricularia oryzae), cereal eyespot(Pseudocercosporelia herpotrichoides), rice sheath blight (Pelliculariasasakii), grey mould (Botrytis cinerea), damping off (Rhizoctoniasolani), wheat brown rust (Puccinia recondita), late tomato or potatoblight (Phytophthora infestans), apple scab (Venturia inaequalis), glumeblotch (Leptosphaeria nodorum). Other fungi against which the compoundsmay be active include other powdery mildews, other rusts, and generalpathogens of Deuteromycete, Ascomycete, Phycomycete and Basidiomyceteorigin.

The invention thus also provides a method of combating fungi at a locusinfested or liable to be infested therewith, which comprises applying tothe locus a compound of formula I.

The invention also provides an agricultural composition comprising acompound of formula I in admixture with an agriculturally acceptablediluent or carrier.

The composition of the invention may of course include more than onecompound of the invention.

In addition, the composition can comprise one or more additional activeingredients, for example compounds known to possess plant-growthregulant, herbicidal, fungicidal, insecticidal or acaricidal properties.Alternatively the compound of the invention can be used in sequence withthe other active ingredient.

The diluent or carrier in the composition of the invention can be asolid or a liquid optionally in association with a surface-active agent,for example a dispersing agent, emulsifying agent or wetting agent.Suitable surface-active agents include anionic compounds such as acarboxylate, for example a metal carboxylate of a long chain fatty acid;an N-acylsarcosinate; mono- or di-esters of phosphoric acid with fattyalcohol ethoxylates or salts of such esters; fatty alcohol sulfates suchas sodium dodecyl sulfate, sodium octadecyl sulfate or sodium cetylsulfate; ethoxylated fatty alcohol sulfates; ethoxylated alkylphenolsulfates; lignin sulfonates; petroleum sulfonates; alkyl-aryl sulfonatessuch as alkyl-benzene sulfonates or lower alkylnaphthalene sulfonates,e.g. butyl-naphthalene sulfonate; salts of sulfonatednaphthalene-formaldehyde condensates; salts of sulfonatedphenol-formaldehyde condensates; or more complex sulfonates such as theamide sulfonates, e.g. the sulfonated condensation product of oleic acidand N-methyl taurine or the dialkyl sulfosuccinates, e.g. the sodiumsulfonate of dioctyl succinate. Nonionic agents include condensationproducts of fatty acid esters, fatty alcohols, fatty acid amides orfatty-alkyl- or alkenyl-substituted phenols with ethylene oxide, fattyesters of polyhydric alcohol ethers, e.g. sorbitan fatty acid esters,condensation products of such esters with ethylene oxide, e.g.polyoxyethylene sorbitan fatty acid esters, block copolymers of ethyleneoxide and propylene oxide, acetylenic glycols such as2,4,7,9-tetramethyl-5-decyne-4,7-diol, or ethoxylated acetylenicglycols.

Examples of a cationic surface-active agent include, for instance, analiphatic mono-, di-, or polyamine as an acetate, naphthenate or oleate;an oxygen-containing amine such as an amine oxide or polyoxyethylenealkylamine; an amide-linked amine prepared by, the condensation of acarboxylic acid with a di- or polyamine: or a quaternary ammonium salt.

The compositions of the invention can take any form known in the art forthe formulation of agrochemicals, for example, a solution, a dispersion,an aqueous emulsion, a dusting powder, a seed dressing, a fumigant, asmoke, a dispersible powder, an emulsifiable concentrate or granules.Moreover it can be in a suitable form for direct application or as aconcentrate or primary composition which requires dilution with asuitable quantity of water or other diluent before application.

An emulsifiable concentrate comprises a compound of the inventiondissolved in a water-immiscible solvent which is formed into an emulsionwith water in the presence of an emulsifying agent.

A dusting powder comprises a compound of the invention intimately mixedand ground with a solid pulverulent diluent, for example, kaolin.

A granular solid comprises a compound of the invention associated withsimilar diluents to those which may be employed in dusting powders, butthe mixture is granulated by known methods. Alternatively it comprisesthe active ingredient absorbed or adsorbed on a pre-granular diluent,for example, Fuller's earth, attapulgite or limestone grit.

Wettable powders, granules or grains usually comprise the activeingredient in admixture with a suitable surfactant and an inert powderdiluent such as china clay.

Another suitable concentrate is a flowable suspension concentrate whichis formed by grinding the compound with water or other liquid, a wettingagent and a suspending agent.

The concentration of the active ingredient in the composition of thepresent invention, as applied to plants is preferably within the rangeof 0.0001 to 1.0 per cent by weight, especially 0.0001 to 0.01 per centby weight. In a primary composition, the amount of active ingredient canvary widely and can be, for example, from 5 to 95 per cent by weight ofthe composition.

In the method of the invention, the compound is generally applied toseeds, plants or their habitat. Thus, the compound can be applieddirectly to the soil before, at or after drilling so that the presenceof active compound in the soil can control the growth of fungi which mayattack seeds. When the soil is treated directly the active compound canbe applied in any manner which allows it to be intimately mixed with thesoil such as by spraying, by broadcasting a solid form of granules, orby applying the active ingredient at the same time as drilling byinserting it in the same drill as the seeds. A suitable application rateis within the range of from 5 to 1000 g per hectare, more preferablyfrom 10 to 500 g per hectare.

Alternatively, the active compound can be applied directly to the plantby, for example, spraying or dusting either at the time when the fungushas begun to appear on the plant or before the appearance of fungus as aprotective measure. In both such cases the preferred mode of applicationis by foliar spraying. It is generally important to obtain good controlof fungi in the early stages of plant growth as this is the time whenthe plant can be most severely damaged. The spray or dust canconveniently contain a pre- or post-emergence herbicide if this isthought necessary. Sometimes, it is practicable to treat the roots of aplant before or during planting, for example, by dipping the roots in asuitable liquid or solid composition. When the active compound isapplied directly to the plant a suitable rate of application is from0.025 to 5 kg per hectare, preferably from 0.05 to 1 kg per hectare.

In addition, the compounds of the invention can be applied to plants, orparts thereof, which have been genetically modified to exhibit a traitsuch as fungal and/or herbicidal resistance.

The general formula I covers thieno[3,2-d]pyrimidine derivatives II,thieno[3,4-d]pyrimidine derivatives III, and thieno[2,3-d]pyrimidinederivatives IV.

Compounds of formula IIc, i.e. compounds of general formula II where R¹s hydrogen and Z is oxygen, can be prepared from compound V in two stepsaccording to reaction Scheme 1. Compounds of formula V may be preparedby a number a methods; see for example references and reviews inComprehensive Heterocyclic Chemistry, Eds Katritzky A R and Rees C W,(4), 863-934 and Comprehensive Heterocyclic Chemistry II, Eds KatritzkyA R, Rees C W and Scriven E F V, (2) 607-678.

Equivalent compounds of general formula III and IV can be made mutatismutandis in similar manner.

Compounds of formula IId, i.e. compounds of general formula II where R¹is hydrogen, Z is oxygen, R³ is a group inert to lithiumdiisopropylamide and R⁴ is a substituent E, can be prepared in foursteps from lie according to reaction Scheme 2 wherein E is introducedusing electrophilic substitution. Reaction conditions for introducingsubstituent E involve treatment of intermediate VIII with lithiumdiisopropylamide followed by addition of a suitable electrophile source.For example when E is —CH(R)OH, CN, bromine or methyl, the electrophilesource is respectively, RC(═O)H, tosyl cyanide, N-bromosuccinimide ormethyl iodide. When the group E is —CH(R)OH, elimination of water mayoccur to form the corresponding compound II where E is alkenyl.

Compounds of formula IIf, i.e. compounds of formula II where R¹ ishydrogen and Z is sulfur can, be made in two steps from IIa, by reactionwith phosphorus oxychloride followed by treatment with sodiumhydrosulfide according to reaction Scheme 3.

Equivalent compounds of general formula III and IV can be made mutatismutandis in similar manner.

Compounds of formula IIg, i.e. compounds of general formula II where R³is a halogen, can be prepared according to reaction Scheme 4. When thehalogen is bromine or chlorine, preferred reaction conditions comprisereacting IIh with bromine or chlorine in glacial acetic acid.

Compounds of formula IIb, i.e. compounds of formula II where Z isoxygen, can be prepared from compounds of formula IIa, i.e. compounds offormula II where Z is oxygen and R¹ is hydrogen, by reacting IIa withbase followed by treatment with R¹X where X is a leaving group. Forexample when R¹ is alkyl, preferred reaction conditions comprisetreating IIa. with sodium hydride followed by an alkyl iodide (Scheme5).

Equivalent compounds of general formula III and IV can be made mutatismutandis in similar manner.

Compounds of formula IIi, i.e. compounds of formula II where R¹ ishydroxy and Z is oxygen, may be prepared in three steps starting fromcompound V according to reaction Scheme 6.

Equivalent compounds of general formula III and IV can be made mutatismutandis in similar manner.

Compounds of formula IIj, i.e. compounds of formula II where R¹ isR^(a)O, may be prepared according to Scheme 7 by reacting compounds offormula IIk with a suitable base, preferably sodium hydride followed byR^(a)X where X is a leaving group.

Equivalent compounds of general formula III and IV can be made mutatismutandis in similar manner.

Compounds of formula IIm, i.e. compounds of formula II where R¹ isacyloxy, may be prepared according to Scheme 8 by reacting compounds offormula IIk with the corresponding acyl chloride.

Equivalent compounds of general formula III and IV can be made mutatismutandis in similar manner.

Compounds of formula IIn, i.e. compounds of general formula II where R¹is NH₂ and Z is oxygen, can be prepared by reacting compounds of formulaIX with hydrazine hydrochloride according to reaction Scheme 9. SeeScheme 6 for the preparation of IX.

Equivalent compounds of general formula III and IV can be made mutatismutandis in similar manner.

Compounds of formula IIp, i.e. compounds of general formula II where R¹is NH-acyl, can be prepared by reacting compounds of formula IIq withthe corresponding acyl halide according to reaction Scheme 10.

Equivalent compounds of general formula III and IV can be made mutatismutandis in similar manner.

Compounds of formula IIr, i.e. compounds of general formula II where R¹is —N═CHR and Z is oxygen, can be prepared according to reaction Scheme11. R is preferably an aromatic group and R^(d) is preferably a loweralkyl group.

Equivalent compounds of general formula III and IV can be made mutatismutandis in similar manner.

Compounds of IIs, i.e. compounds of general formula III where R³ isbromine, can be prepared by treating compound of formula lift withbromine in glacial acetic acid heated under reflux for 2 hours.Continued heating for 5 hours gives the dibrominated compound IIIu,where R³ and R⁴ are both bromine (Scheme 12).

Compounds of general formula IIb, i.e. compounds of formula II where Zis oxygen, can be converted to the corresponding compounds IIv where Zis sulfur by reaction with P₂S₅. The reaction is shown in Scheme 13.

Equivalent compounds of general formula III and IV can be made mutatismutandis in similar manner.

Other methods will be apparent to the chemist skilled in the art as willbe the methods for preparing starting materials and intermediates.

The invention is illustrated in the following Examples. Structures ofisolated novel compounds were confirmed by NMR and/or other appropriateanalyses.

EXAMPLE 1 6-Bromo-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (Compound 8a)

A solution of the product from step c) (0.22 g), hydrobromic acid (2 ml,46% solution) in glacial acetic acid (10 ml) was heated under reflux for6 hours. On cooling the mixture was diluted with water and the mixturefiltered. The solid was washed with water and air-dried to give thetitle product, m.p. 238-240° C.

Preparation of Starting Materials

a) 4-Chlorothieno[3,2-d]pyrimidine

A mixture of compound 1h (see Table H) (10 g) and phosphorousoxychloride (100 ml) was heated under reflux for 5 hours. On cooling thesolution was evaporated to dryness and the residue added to ice-water(with caution). The mixture was extracted with ethyl acetate and thenwith dichloromethane. The organic portions were washed with sodiumhydrogen carbonate solution followed by brine, dried (MgSO₄) andfiltered through a silica pad. The filtrate was evaporated to give thetitle product.

b) 4-Methoxythieno[3,2-d]pyrimidine

To a suspension of sodium hydride (2 g 60% in oil) in dry dioxane (80ml) at room temperature was added methanol (6 ml). When effervescencehad subsided the product from step a) (5 g) was added and the reactionmixture stirred overnight at room temperature. The mixture was pouredinto water and extracted with ethyl acetate (×3). The combined organicextracts were washed with brine, dried (MgSO₄), filtered and the solventremoved to give the title product, m.p. 92-94° C.

6-Bromo-4-methoxythieno[3,2-d]pyrimidine

To a solution of the product from step b) (0.5 g) in dry tetrahydrofuran(20 ml) was added lithium diisopropylamide (1.53 ml, 2 M) at −78° C. andstirring continued for 45 minutes. A solution of N-bromosuccinimide (0.6g) in dry tetrahydrofuran (10 ml) was added dropwise at −78° C. and thenallowed to attain room temperature over one hour. The reaction mixturewas poured into ice-water and extracted with ethyl acetate (×3). Theorganic extracts were washed with brine, dried (MgSO₄), filtered and thesolvent removed. The resulting solid was purified by silica gelchromatography eluting with light petroleum (60-80° C.)/ethyl acetate(2:1) to give the title product, m.p. 111-113° C.

EXAMPLE 2 7-Bromo-6-methyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one(Compound 2a)

A stirred solution of compound 7a (see Table A) (2.1 g), bromine (0.2ml) and glacial acetic acid (2 ml) was heated under reflux for 5 hours.On cooling, the reaction mixture was poured into water. The mixture wasthen filtered to give a solid which was washed with water and then lightpetroleum (b.p. 60-80° C.) and dried to give the title product, m.p.320-322° C.

The following compounds of formula IIa in Table A, i.e. compounds offormula II where Z is oxygen and R¹ is hydrogen, may be prepared by oneor more methods analogous to those of Examples 1 and 2.

TABLE A (IIa)

Cmp R³ R⁴ m.p./° C. 1a Br H 330-332 2a Br Me 320-322 3a Cl H 298-301 4aCl Cl 278-289 5a Br Ph 329-331 6a Br tBu 299-301 7a H Me 201-203 8a H Br238-240 9a H vinyl 84-88 10a Me Br 246-249 11a Br Me₃Si 293-296

EXAMPLE 3 3,6-Dimethyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one (Compound19b)

To a stirred suspension of sodium hydride (0.05 g, 60% in oil) in dryN-methylpyrrolidinone (2 ml) at room temperature was added compound 7a(0.1 9) and stirring continued for 15 minutes. Iodomethane (0.1 ml) wasthen added and stirring continued at room temperature overnight. Waterwas added and the mixture extracted with ethyl acetate (×3). The organicextracts were combined and dried (MgSO₄), filtered through a silica padand the solvent removed. The residue was triturated with diisopropylether to give the title product, m.p. 188-190° C.

The following compounds of formula IIb in Table B, i.e. compounds offormula II where Z is oxygen may be prepared by one or more methodsanalogous to those of Example 3.

TABLE B (IIb)

Cmp R¹ R³ R⁴ m.p./° C. 1b Me Br H 212-214 2b benzyl Br H 132-134 3ballyl Br H 96-98 4b iBu Br H 116-118 5b

Br H 333-338 6b iPr Br H 148-150 7b 3-PhO-benzyl Br H 117-120 8b2-CF₃-benzyl Br H 137-139 9b 4-Cl-benzyl Br H 162-164 10b2,6-diCl-benzyl Br H 181-183 11b 4-MeO-benzyl Br H 159-161 12b propargylBr H 144-146 13b 2,4,6-triCl-phenoxyethyl Br H 161-163 14b —CH₂C(═O)OMeBr H 170-172 15b —CH₂C(═O)OBut Br H 169-171 16b —CH₂C(═O)OH Br H 248-25017b Me H H 168-169 18b —CO₂Et Br H 126-128 19b Me H Me 188-190 20b

Br H 230-232 21b —CH₂(C═O)Ph Br H 195-196 22b —CH₂CN Br H 199-201 23b3,4-diCl-benzyl Br H 191-192 24b 2-Cl-benzyl Br H 127-131 25b2,4-diCl-benzyl Br H 146-147 26b Et Br H 156-159 27b 4-Br-benzyl Br H170-175 28b 4-tBu-benzyl Br H 204-207 29b 2,4-diCl-benzyl Me H 158-15930b benzyl Me H 126-127 31b 2-CF₃-benzyl Me H 133-134 32b 3-PhO-benzylMe H 98-99 33b 2-Cl-benzyl Me H 133-134 34b 4-Cl-benzyl Me H 169-170 35b

Me H 224-225 36b 4-Br-benzyl Me H 166-167 37b 3,4-diMeO-benzyl Me H136-137 38b 4-tBu-benzyl Me H 201-202 39b 2,4-diMe-benzyl Br H 124-12640b 3,4-diMeO-benzyl Br H 190-193 41b

Br H 201-206 42b

Br H 196-200 43b 3-CF₃-benzyl Br H 150-152 44b —(CH₂)₂OC(═O)Me Br H123-124 45b —CH(Ph)—C(═O)OMe Br H gum 46b —CH(CO₂Et)₂ Br H 92-93 47b—CH(iPr)CO₂Et Br H 93-94 48b —CH(Me)CO₂Et Br H 122-123 49b —CH(Pr)CO₂EtBr H 82-84 50b

Br H 248-250 51b but-2-eneyl Br H 133-134 52b —CH₂C(═O)NH₂ Br H 277-28153b 3-NO₂-benzyl Br H 216-218 54b phenylpropyl Br H 81-83 55b decyl Br H50-52 56b 4-NO₂-phenyl Br H 285-290 57b 2,4-diCl-benzyl Br tBu 149-15058b 2-CF₃-benzyl Br tBu 172-173 59b 3-PhO-benzy Br tBu 123-124 60b2-Cl-benzyl Br tBu 160-161 61b

Br tBu 209-210 62b 4-Cl-benzyl Br tBu 116-117 63b 4-Br-benzyl Br tBu121-122 64b 4-tBu-benzyl Br tBu 172-173 65b benzyl Br tBu oil 66b3,4-diMeO-benzyl Br tBu oil 67b Me Br tBu 133-134 68b Me Br Ph 202-20469b 3-Cl-5-CF₃-2-pyridyl Br tBu 202-203 70b 3-Ph-1,2,4-thia- Br H270-272 diazol-5-yl 71b Me Me H 194-195 72b 3-Cl-5-CF₃-2-pyridyl Br H180-183 73b Me —(CH)₃—N— 236-237 74b 2-NO₂-4-CF₃-phenyl Br H 212-214

EXAMPLE 4 7-Bromo-3-hydroxy-3,4-dihydrothieno[3,2-d]pyrimidin-4-one(Compound 2c)

A solution of the starting material (1.4 g) and ethyldiisopropylamine(0.65 g) in 1,4-dioxan (20 ml) was heated under reflux for 24 hours. Oncooling the reaction mixture was acidified with dilute hydrochloric acidand water (20 ml) was added. The solution was filtered to give a solidwhich was washed and dried to give the title product, m.p. 244-247° C.

Preparation of Starting Material

a) Methyl 4-bromo-3-(dimethylaminomethylene)amino-2-thenoate

A solution of methyl 3-amino-4-bromo-2-thenoic acid (for preparation seeJ. Gen. Chem. USSR, (1964), 34, 961) (5 g) and N,N-dimethylformamidedimethyl acetal (5 g) in toluene (30 ml) were heated under reflux for 8hours. On cooling the solvent was removed and the residue purified bysilica gel chromatography eluting with ethyl acetate: light petroleum(b.p. 60-80° C.) (1:3) to give the title compound.

b) Methyl 4-bromo-3-[(hydroxyiminomethyl)amino]-2-thenoate

To a stirred solution of the product from step a) (1.0 g) in methanol(10 ml) was added hydroxylamine hydrochloride (0.47 g) at roomtemperature. After 10 minutes, stirring was stopped and the mixtureallowed to stand at room temperature for 3 hours. The mixture wasfiltered to give a solid, which was washed with chilled methanol (3 ml)and dried to give the title product.

EXAMPLE 57-Bromo-3-(4-methoxy)benzyloxy-3,4-dihydrothieno[3,2-d]pyrimidin-4-one(Compound 3c)

To a stirred suspension of sodium hydride (0.053 g, 60% in oil) in dryNMP (5 ml) at room temperature was added the product from Example 4(0.325 g), and stirring was continued until effervescence ceased.4-Methoxybenzyl chloride (0.2 g) was then added and the reaction mixturewas stirred for 24 hours at room temperature. The reaction mixture waspoured into water and the resulting white precipitate was filtered togive a white solid. This white solid was dissolved in dichloromethaneand dried (MgSO₄). Removal of the solvent gave the title product, m.p.178-180° C.

EXAMPLE 6 3-Acetoxy-7-bromo-3,4-dihydrothieno[3,2-d]pyrimidin4-one(Compound 4c)

To a solution of acetyl chloride (0.234 g) in dry tetrahydrofuran (3 ml)was added a solution of the product from Example 4 (0.741 g) in pyridine(0.237 g) and N-methylpyrrolidone (5 ml) at room temperature. Thesolution was stirred at room temperature for 3 days and then poured intowater (15 ml). The resulting precipitate was filtered, washed with waterand dried to give title product, m.p. 159-162° C.

The following compounds of formula IIx in Table C, i.e. compounds offormula II where Z is oxygen, R¹ is OR^(a), R³ is bromine and R⁴ ishydrogen, may be prepared by methods analogous to those of Examples 4 to6.

TABLE C (IIx)

Cmp R^(a) m.p./° C. 1c Me 152-154 2c H 244-247 3c

178-180 4c —C(═C)Me 159-162

EXAMPLE 7 3-Amino-7-bromo-3,4-dihydrothieno[3,2-d]pyrimidin-4-one(Compound 6d)

To a stirred solution of the product from step a) Example 4 (1.1 g) inmethanol (7 ml) was added hydrazine hydrochloride (0.54 g) and stirringwas continued for 1 hour. The reaction mixture was filtered to give awhite solid which was washed with water and dried to give the titlecompound, m.p. 181-183° C.

EXAMPLE 8 3-Acetamido-7-bromo-3,4-dihydrothieno[3,2-d]pyrimidin-4-one(Compound 3d)

To a stirred solution of acetyl chloride (0.16 g) in 1,4-dioxan (2 ml)was added a solution of the product from Example 7 (0.5 g) in pyridine(0.16 g) and N-methylpyrrolidinone (0.5 ml) and stirring was continuedfor 1 hour at room temperature. Water was added and the mixture wasfiltered to give a solid which was dried to give the title product, m.p.273° C.

EXAMPLE 93-(4-Chlorobenzylidene)amino-7-methyl-3,4-dihydrothieno[3,2-d]pyrimidin4-one(Compound 4d)

A solution of the product from step b (1.6 g), trimethyl orthoformate(10 ml), p-toluene sulfonic acid (catalytic) in xylene (100 ml) washeated under reflux for 2 hours. On cooling, the reaction mixture wasevaporated to dryness and recrystallised from toluene to give the titleproduct, m.p. 213-215° C.

Preparation of Starting Materials

a) 3-Amino-4-methyl-2-thiophenecarbohydrazide

A solution of methyl 3-amino-4-methyl-2-thenoate (25 g) and hydrazinehydrate (20 ml) in butanol (150 ml) was heated under reflux for 18hours. On cooling the solvent was removed and the residue wasrecrystallised from toluene to give the title product, m.p. 141-143° C.

b) N²-(4-chlorobenzylidene)-3-amino4-methyl-2-thiophenecarbohydrazide

A solution of the product from step a) (3,4 g) and p-chlorobenzaldehyde(2.8 g) in ethanol (200 ml) was heated under reflux for 2 hours. Oncooling the reaction mixture was filtered to give the title product.

The following compounds of formula IIy in Table D, i.e. compounds offormula II where Z is oxygen and R⁴ is hydrogen, may be prepared by oneor methods analogous to those of Examples 7 to 9.

TABLE D (IIy)

Cmp R¹ R³ m.p./° C. 1d —N═CHOMe H 120-122 2d

H 204-205 3d —NHC(═O)Me Br 273 4d

Me 213-215 5d

Br 235-237 6d NH₂ Br 181-183

EXAMPLE 10 7-Bromo-3,4-dihydrothieno[3,2-d]pyrimidin-4-thione (Compound1e)

A solution of 7-bromo-4-chlorothieno[3,2-d]pyrimidine (see below forpreparation) (2.0 g), sodium hydrosulfide hydrate (0.66 g) andN-methylpyrrolidinone (10 ml) was heated at 102° C. for 1 hour. Water(500 ml) and ethyl acetate (500 ml) were added and stirred for 1hour.The layers were separated and the aqueous phase extracted with ethylacetate (300 ml). The combined organic extracts were washed with brine(300 ml), dried (MgSO₄), treated with activated charcoal, then filteredthrough a silica pad and the solvent removed to give the title product,m.p. 328° C.

Preparation of Starting Materials 7-Bromo4-chlorothieno[3,2-d]pyrimidinewas prepared in analogous fashion to Example 1 step a), starting fromcompound 1a. EXAMPLE 11 3,4-Dihydrothieno[3,4-d]pyrimidin-4-one(Compound 1f)

A stirred mixture of methyl 4-formamido-3-thenoate (see below) (3.39 g)and ammonium formate (3,4 g) in formamide (5 ml) was heated at 140° C.for 7 hours. On cooling, the mixture was poured into water, and themixture filtered to give a solid which was washed with water followed bylight petroleum (b.p. 60-80° C.) and air dried to give the titleproduct, m.p. 275-278° C.

Preparation of Starting Materials

Methyl 4-Formamido-3-thenoate

A stirred solution of methyl 4-amino-3-thenoate (4 g), sodium acetatetrihydrate (2.8 g) and formic acid (27 ml) was heated at 95° C. for 1hour. On cooling the solution was poured into water, and the solutionfiltered to give the title product as a solid.

EXAMPLE 12 5,7-Dibromo-3,4-dihydrothieno[3,4-d]pyrimidin4-one (Compound2f)

A solution of the product from Example 11 (0.9 g) and excess bromine(0.4 ml) in glacial acetic acid (100 ml) were heated at 100° C. for 5hours until no bromine remained. On cooling the solvent was removed andthe residue was dried. The residue was recrystallised from acetic acidto give the title product, m.p. >250° C.

EXAMPLE 13 7-Bromo-3,4-dihydrothieno[3,4-d]pyrimidin4-one (Compound 3f)

A solution of the product from Example 12 (0.9 g) and bromine (0.3 ml)in glacial acetic acid (100 ml) were heated at 100° C. for 2 hours. Oncooling the solvent was removed and the residue was dried. The residuewas recrystallised from acetic acid to give the title product, m.p.226-229° C.

EXAMPLE 14 3,4-Dihydrothieno[2,3-d]pyrimidin4-one (Compound 5g)

The product from step b) (4.38 g) and ammonium formate (4.38 g) informamide (18 ml) was heated with stirring at 150° C. for 7 hours. Themixture was cooled and poured into water. The precipitated solid wasfiltered, washed with water followed by dichloromethane and dried togive the title product, m.p. 256-8° C.

Preparation of Starting Materials

a) Ethyl 2-Amino-3-thenoate

Piperidine (20.7 ml) was added dropwise with stirring to a mixture of2,5-dihydroxy-1,4-dithiane (17.5 g) and ethyl cyanoacetate (23.7 g). Themixture was stirred at room temperature for 4 hours and then allowed tostand overnight. It was filtered and the filtrate evaporated to dryness.The residue was dissolved in ether, filtered and evaporated to dryness.The residue was triturated with light petroleum (b.p. 60-80° C.)containing a small amount of ethyl acetate. The gummy solid obtained waspurified by silica gel column chromatography and the semi-solid productwas triturated with water, filtered and washed with light petroleum(b.p. 60-80° C.) and dried to give the title product.

b) Ethyl 2-Formamido-3-thenoate

The product from step a) (14.6 g) was added to a mixture of aceticanhydride (24.3 ml) and formic acid (24.3 ml) with stirring and cooling.The mixture was stirred at room temperature for 4 hours and evaporatedunder reduced pressure. The residue was dissolved in ether and cooled indry ice. The precipitate was filtered off and dried to give the titleproduct.

EXAMPLE 15 6-Bromo-3,4-dihydrothieno[2,3-d]pyrimidin-4-one (Compound 6g)

The product from Example 14 (0.75 g) was added to glacial acetic acid(10 ml) and heated with stirring until it dissolved. Bromine (0.75 ml)was then added and the mixture immediately set solid. More acetic acidwas added and the mixture broken up. It was then heated at 80° C. for 6½hours, cooled and poured into ice-water. The solid was filtered andwashed with water followed by dichloromethane and dried to give thetitle product, m.p. 304° C.

The following compounds of formula IVz in Table G, i.e. compounds offormula IV where Z is oxygen, may be prepared by one or more methodsanalogous to those of

EXAMPLES 3, 14 and 15.

TABLE G (IVz)

Cmp R¹ R³ R⁴ m.p./° C. 1g H H Ph 2g Me H Me 132-133 3g H Br Ph 271-2734g H H Me 235-237 5g H H H 256-258 6g H Br H 301-304 7g H H 2-thienyl 8g3-PhO-benzyl H Me oil 9g H Br Me 241-243 10g 2,4-diCl-benzyl H Me130-131 11g Benzyl H Me 123-124 12g 2-CF₃-benzyl H Me 106-107 13g2-Cl-benzyl H Me 124-125 14g 4-Cl-benzyl H Me 143-144 15g

H Me 180-181 16g 4-Br-benzyl H Me 155-156 17g 3,4-diMeO-benzyl H Me161-162 18g 4-tBu-benzyl H Me 160-161

The following compounds of formula IIa in Table H, i.e. compounds offormula II where Z is oxygen and R¹ is hydrogen, may be prepared bymethods analogous to those of Example 14 replacing ethyl2-amino-3-thenoate in step a) with the corresponding 3-amino-2-thenoate.

TABLE H (IIa)

Cmp R³ R⁴ m.p./° C. 1h H H 228-230 2h Me H 243-246 3h —(CH)₃N— 340-3424h H Ph 271-273 5h H tBu 235-237 6h Ph H 235-237 7h H 4-Cl-phenyl 8h PhCF₃ 9h H 4-F-phenyl

Test Example

Compounds were assessed for activity against one or more of thefollowing:

Erysiphe graminis f sp. tritici: wheat powdery mildew

Phytophthora infestans: late tomato blight

Pyricularia oryzae: rice blast

Leptosphaeria nodorum: glume blotch

Plasmopara viticola: downy mildew of vines

Aqueous solutions or dispersions of the compounds at the desiredconcentration, including a wetting agent, were applied by spray or bydrenching the stem base of the test plants, as appropriate. After agiven time, plants or plant parts were inoculated with appropriate testpathogens and kept under controlled environmental conditions suitablefor maintaining plant growth and development of the disease. After anappropriate time, the degree of infection of the affected part of theplant was visually estimated. Compounds are assessed on a score of 1 to3 where 1 is little or no control, 2 is moderate control and 3 is goodto total control. At a concentration of 500 ppm (w/v) or less, thefollowing compounds scored 2 or more against the fungi specified.

Ervsiphe graminis f sp. tritici

3a, 12a, 1b, 5b, 6b, 7b, 8b, 9b, 10b, 11b, 13b, 14b, 16b, 24b, 25b, 26b,27b, 41b, 43b, 45b, 47b, 50b, 52b, 53b, 54b, 55b, 61b, 66b, 2f, 3f and5g.

Phytophthora infestans

1a, 8a, 14b, 15b, 2d, 3f and 9h.

Pyricularia orvzae

1a, 3a,4a, 6a, 8a, 10a, 12a, 1b, 4b, 5b, 6b, 7b, 8b, 9b, 10b, 11b, 18b,20b, 21b, 22b, 25b, 26b, 27b, 30b, 40b, 41b, 43b, 44b, 45b, 46b,47b,48b, 49b, 50b, 51b, 52b, 54b, 55b, 57b, 63b, 65b, 66b, 2c, 2d, 6d, 1e,4g, 5g, 6g, 8g, 9g, 17g, 18g, 1h and 2h.

Leotosphaeria nodorum

2b, 5b, 6b, 7b, 9b, 10b, 11b, 13b, 18b, 28b, 29b, 33b, 39b, 41b, 43b,51b, 1f, 6g, 8g, 4h and 8h.

Plasmonara viticola

1b, 5b, 12b, 14b, 15b, 18b, 20b, 21b, 22b, 23b, 28b, 40b, 41b, 1f, 2f,3f and 10g.

What is claimed is:
 1. A method of combating fungi comprising applyingto a locus infected or liable to be infected an effective fungicidalamount of a compound of general formula

wherein R¹ is hydrogen, hydroxy, acyl, acyloxy, optionally substitutedamino, R^(a), R^(a) ₃Si, R^(a)S or R^(a)O, where R^(a) is optionallysubstituted alkyl, optionally substituted alkenyl, optionallysubstituted alkynyl, optionally substituted cycloalkyl, optionallysubstituted cycloalkenyl, optionally substituted aryl or optionallysubstituted heterocyclyl; Z is oxygen or sulfur; M is a thiophene ring;and R³ and R⁴, which may be the same or different, have the same meaningas R^(a) or can be optionally substituted amino, hydrogen, halogen,cyano, nitro or a group OR^(c) or S(O)_(m)R^(c), where R^(c) has thesame meaning as R^(a) or is hydrogen or acyl and m is 0, 1 or 2; or R³and R⁴ together with the atoms to which they are attached form anoptionally substituted carbocyclic or heterocyclic ring; wherein anyheterocyclic ring has 5, 6 or 7 ring members and up to 4 hetero atomsand is selected from the group consisting of furyl, thienyl, pyrrolyl,pyrrolinyl, pyrrolindinyl, imidazolyl, dioxolanyl, oxazolyl, thiazolyl,imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl,pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, pyranyl, pyridyl, piperidinyl, dioxanyl, morpholino,dithianyl, thiomorpholino, pyridazinyl, pyriridinyl, pyrazinyl,piperzinyl, triazinyl, thiazolinyl, benzimidazolyl, tetrazolyl,benzoxazolyl, imidazopyridinyl, 1,3-benzoxazinyl, 1,3-benzothiazinyl,oxazolopyridinyl, benzofuranyl, quinolinyl, quinazolinyl, quinoxalinyl,sulfolanyl, dihydroquinazolinyl, benzothiazolyl, phthalimido,benzofuranyl, azepinyl, oxazepinyl, thiazepinyl, tetrahydrofuryl,diazepinyl and benzodiazepinyl; wherein any cycloalkyl, cycloalkenyl orcycloalkynyl group has 3 to 7 carbon atoms; any substituent when presenton any alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or cycloalkynylis halogen, cyano, optionally substituted alkoxy, optionally substitutedalkylthio, mercapto, hydroxy, nitro, optionally substituted amino, acyl,acyloxy, acylthio, optionally substituted phenyl, optionally substitutedheterocyclyl, optionally substituted phenylthio, optionally substitutedphenoxy, optionally substituted heterocycloloxy, optionally substitutedheterocyclythio; any cycloalkyl, cycloalkenyl or cycloalkynyl isoptionally substituted by optionally substituted by optionallysubstituted by alkyl, alkenyl or alkynyl and vice versa; substituentswhen present on any phenyl or heterocyclyl group may be the same ordifferent and are R^(a)—(X)_(n)— where X is oxygen or sulfur and n is 0or 1, optionally substituted amino, hydroxy, halogen, cyano, nitro,acyl, or two adjacent groups together with the carbon atoms to whichthey are attached form an optionally substituted benzo or heterocyclicring and the heterocyclic group may be also be substituted by oxo orimino, substituents when present on an amino group are one or two R¹groups or two substituents form a 5 to 7 membered ring which optionallycontains other hetero atoms and can be substituted in the same manner asheterocyclyl; together with tautomers where R¹ is hydrogen.
 2. Themethod of combating fungi according to claim 1 wherein Z is oxygen. 3.The method of combating fungi according to claim 2 wherein R¹ ishydrogen 2-oxotetrahydrofuranyl or optionally substituted alkyl.
 4. Themethod of combating fungi according to claim 3, wherein R¹ is hydrogen.5. The method of combating fungi according to claim 3, wherein R¹ isC₁-C₅-alkyl, optionally substituted by alkoxycarbonyl, alkanoyloxy,cyano or phenyl, itself optionally substituted by alkyl, alkoxy,haloalkyl or halogen.
 6. The method of combating fungi according toclaim 5 wherein R³ and R⁴, which may be the same or different, arehydrogen or halogen.
 7. The method in combating fungi according to claim1, wherein the compound is a thieno[3,2-d]pyrimidine derivative ofclaim
 1. 8. The method of combating fungi according to claim 1, whereinany alkyl group has 1 to 10 carbon atoms and any alkenyl or alkynylgroup has 2 to 7 carbon atoms; and any acyl is the residue of carboxylicacid, sulfur containing acid and phosphorus containing acid.
 9. Themethod of combating fungi according to claim 8, wherein R¹ is hydrogen,2-oxo-tetrahydrofuranyl or optionally substituted alkyl of 1 to 7 carbonatoms and wherein R³ and R⁴, which may be the same or different, arehydrogen or halogen.
 10. The method of combating fungi according toclaim 9, wherein R¹ is alkyl of 1 to 5 carbon atoms optionallysubstituted by phenyl, itself optionally substituted by alkoxy,haloalkyl or halogen, and wherein one of R³ or R⁴ is hydrogen and theother is halogen.
 11. A method of combating fungi comprising applying toa locus infected or liable to be infected an effective fungicidal amountof 7-bromo-3-methyl-3,4-dihydrothieno[3,2-d]pyrimidin-4-one.
 12. Amethod of combating fungi comprising applying to a locus infected orliable to be infected an effective fungicidal amount of a compound ofthe formula

wherein R¹ is alkyl of 1 to 5 carbon atoms optionally substituted byphenyl, itself optionally substituted by alkoxy, haloalkyl or halogen,and wherein one of R³ or R⁴, which may be the same or different, arehydrogen or halogen.